Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy
Authors: Raj K. Maturi, Adam R. Glassman, Kristin Josic, Carl W. Baker, Adam T. Gerstenblith, Lee M. Jampol, Annal Meleth, Daniel F. Martin, Michele Melia, Omar S. Punjabi, Soraya Rofagha, Hani Salehi-Had, Cynthia R. Stockdale, Jennifer K. Sun, David Browning, John Bradley Allen, Andrew N. Antoszyk, Amanda H. Wilson, Brittany A Murphy, Christina J. Fleming, Courtney Mahr, Angela K. Price, Justin Clark, Sarah A. Ennis, Sherry L. Fredenberg, Taylor S. Jones, Monica D. Nayar, Kayla A Bratcher, Kaitlin T. McShea, Erica Breglio, Christina Mutch, Angella K. Gentile, Carol A Shore, Donna McClain, Loraine M. Clark, Lisa A. Jackson, Lynn Watson, Michael D. McOwen, Tracy A. Ross, Uma M. Balasubramaniam, Shannon Stobbe, Yvonne Ramirez, Sara Ahmed, Stephanie Ramirez, Undariya Boldbaatar, Valeria Quintero, Evelyn Ceja, Scott F. Lee, Jesus Cortes, Katie Tran, Mary Ma, Mailan Tran, Nikki Nguyen, Lily Castillo, Janet Reyes, Karen Gasperian, Robert E. Parnes, April L. Stockman, Jennifer Shirey, Kylie Stambaugh, Lora Glaspell, Leslie Toomey, Angie Goldizen, Charles C. Wykoff, David M. Brown, Amy C. Schefler, Ankoor R. Shah, Eric Chen, James C. Major, Matthew S. Benz, Richard H. Fish, Rosa Y. Kim, Tien P. Wong, Jose Munoz, Maura A Estes, Ilsa Ortega, Diana Rodriguez, Daniel Park, Amy Hutson, Garret L Twining, Mireya Serpas, Sadia Y Karani, Stacy M. Supapo, Tyneisha McCoy, Danee Foerster, Calley N. Smith, Belinda A. Almanza, Miguel Oviedo, Melina Vela, Nina A. Webb, Rebecca Yee, Veronica A. Sneed, Heather Koger-Grifaldo, Elizabeth Quellar, Lisa M Wolff, Lindsay Burt, Luis R. Salinas, Miranda F James, Devendra Sharma, Eric N. Kegley, Beau A Richter, Cary A. Stoever, David Garcia, Dante J. Pieramici, Alessandro A. Castellarin, Dilsher Dhoot, Daniel L. Learned, Nathan Steinle, Carmen Carbajal, Gina Hong, Jack Giust, John McDermott, Jamison C Ray, Kevin Card, Kate M McKee, Libby Dahlberg, Marco A Munoz, Nancy Castillo, Laura Budvytyte, Jerry Smith, Kelly Avery, Krisianne Aromin, Aimee H. Shook, Olivia S. Council, Susan Spaeth, Dennis M. Marcus, Harinderjit Singh, Daisy J McCarty, Elizabeth W Simons, Geri K Whitaker, Amina Farooq, Siobhan O. Ortiz, Thomas Bailey, Lindsay Allison Foster, Michele Woodward, Ken Ivey, Jesse J. Jung, Eugene Stephen Lit, Heidi A. Winje, Maria Zamora, Renjini Balakrishnan, Jihyun Kim, Joshua R Machacon, Mae Kwan, Helen Ricks, Caroline Frambach, Denise Joy Bustamante, Anne Grace Dizon, Afsoon Jamali, Maria Miranda, David A. Lightman, Stephen J Saxe, Lorraine White, Ashley M. Harless, Myra K Retrum, Erin Brown, Carolee K. Novak, Holly Fiscus, Stephanie J. Morrow, Charlotte Harris, Thomas Steele, Yesenia Sarmiento, Ron H. Tilford, Jil D Baker, Tracey M. Caldwell, Margaret J. Orr, Mary J. Sharp, Kylie S. Sedberry, Sonya L Alcaraz, Samantha Kettler, Alecia B. Camp, Brian B. Berger, Chirag D. Jhaveri, Saradha Chexal, Gowtham Jonna, Daniela Mariel Wilson, Daniela Vega Pereira, Tina A Seidu, Ivana Gunderson, Ryan M. Reid, Abla M Harara, Valerie Gatavaski, Yong Ren, Christopher C. Stovall, Boris Corak, Robert W. Wong, Peter A. Nixon, Jose A. Martinez, Phillip V. Le, Margaret A. Rodriguez, Chris A. Montesclaros, Corinne C Vargas, Gopal Karsaliya, Cory Mangham, Lloyd Paul Aiello, George S. Sharuk, Miin Irene Roh, Paul G. Arrigg, Paolo S. Silva, Sabera T. Shah, Margaret E. Stockman, Tanya Olesker, Jae W Rhee, Jerry D. Cavallerano, Leila Bestourous, Michael N. Krigman, Mina Sehizadeh, Shireen Glynn, Steve L. Papaconstantinou, Robert W. Cavicchi, William Carli, Konstantina Sampani, Elizabeth S. Weimann, Joseph M. Googe, Nicholas G. Anderson, R. Keith Shuler, Kristina Oliver, Steve Morris, Julie Asher, Justin Walsh, Vicky L. Seitz, Jeff Wheeler, Summer McCoy, Katie Milstead, Raul E. Lince, Sarah M. Oelrich, Caitlin Gilbreath, Hodge A. Griffone, Lakshmana Murthy Kooragayala, Meuzette White-Walker, Minuette S Jackson, Shakirah J Sewell, Chenavia Lewis, Chigozie Nkemka, Samantha Sircar, Kenneth Thompson, Adam Goff, David Isaiah Sierpina, Kakarla V. Chalam, Michael E. Rauser, Samuel C. Kim, Tina L Ramirez, Vivian L Garcia, Raquel Hernandez, Rebecca K Pereyra, Marcia Easterly, Jacqueline V Midgett, Jayson S Paw, Anthoni Tampubolon, Nadiya Thomas, Rene G. Obispo, Adel E Alset, Moises Tellez, Keyvan Koushan, Myuri Jeyabalachandran, Pauline Fung, Arman Amiri, Stephanie Hegarty, Paviya Navanathan, Parita Thakker, Devjani Dutta, Gloria Leung, Jennifer Wong, Michael Henry Brent, Efrem D. Mandelcorn, Swetha Murari, Michelle Moon, Olivera Sutakovic, Lina Chen, Lindsay Hampton-Hampejskova, Bilgin Turhal, Claire Mowatt, Ian Brown, Isaac A Kotei, Susan Bolychuk, Gisela Velez, Javon N Coleman, Madeline Leon, Maa Ahema Parry, Oksana Mykhaylyk, Travis Sweeney, Elizabeth I. Johnson, Nicholas Chang, Nicholas R Mastrodomenico, Michael D. Ortega, Thomas Taylor, Shayina M Calixto, Jean Larkin, Joseph A. Myers, Jhan Carlos Caro, Amanda Aho, Armando Saez, Beatriz LaFountain, Crystal Girard, Christine Manuel, Chandapilla C. Pallipeedikayil, Christina Y. Weng, Tahira Scholle, Peter Rico, Laura A Baker, Becky R. Chatham, Wendy Blacutt, Gihan Romany, Jiping Cai, Annika S. Joshi, April Leger, Jessica Nguyen, Joseph F. Morales, Dana B. Barnett, Matthew A. Cunningham, Elias C. Mavrofrides, Samuel K. S. Houston, Jaya B. Kumar, Martha Haddox, Ramona Gomez, Elaine Rodriguez-Roman, Francisco Pineda, Alma Rodriguez, Chanell Thomas, Dianelis Figueroa, Timothy S Holle, Michael J. Elman, Henry A. Leder, JoAnn Starr, Kate N Kreis, Jennifer L. Belz, Twyla J Robinson, Travis J. Smalls, Teresa Coffey, Alesia K McCalla, Amy Thompson, Christine Ringrose, Dallas R. Sandler, Katherine L Wentz, Joshua Vierheller, Pamela V. Singletary, Perel M. Simpson, Terri Cain, Peter Sotirakos, Ashley M. Metzger, Albert O. Edwards, Allan A. Hunter, Lillian A Carroll, Nicole M Gregorich, Natalie W Kogutkiewicz, Jonathan Wallace, Jessica Zuniga, Ryan G. Lebien, Nicole Muhlnickel, Andrew G. Everett, Daniel F. Rosberger, Nneka O. Brooks, Phuntsho Wangmo, Sandra Acevedo, Sarah Bendarkawi, Sonam Gyaltshen, Joshua A Pickell, Mohammed Yaseen, Yenelda M. Gomez, Alexander J. Brucker, Devica L Bhutani, Joan C. DuPont, Sheri Drossner, Kennedy N Johnson, Judy Chen, Jim M. Berger, Cheryl Devine, Sara Freeman, Shabari S. Seetharam, Ramin Schadlu, Anita Prasad, Brigid Smith, Lindsey Butler, Annemarie Zaborowski, Jacob Michael Hylands, Juan Tonche, Richard I. Breazeale, Francis C. DeCroos, Rohan J. Shah, Devon Ghodasra, Steve W. McBee, Jacob Clements, Kate Menefee, Brianna J Lewis, Courtney Duncan, David Woods, Elizabeth Lisa McDonald, Roger P. Melendrez, Ala Moshiri, Glenn C. Yiu, Cynthia Wallace, Denise C Macias, Angela M. Beliveau, Marisa E. Arnold, Susan Garcia, Sashi Deo, Igor Slabosnitskiy, John Peterson, Karishma Chandra, Paul L. Kaufman, Jessica D. McCluskey, Kathy T. Wynne, Cynthia Weaver, Brandun Watson, Carlos R. Cook, Rosario Romero, Sarah Matloff, Scott Tanner, Kristin Gilbert, Jan Niklas Ulrich, Seema Garg, Elizabeth L. DuBose, Kanika A Bhansali, Cassandra J. Barnhart, Jesse C. Dahringer, Rona Lyn Esquejo, Houston P Sharpe, Debra Cantrell, Sean Grout, Veronica Jones, Jeffrey G. Gross, Victor A. Neamtu, Joel Gross, Vincent Klapper, Amy M. Flowers, Angelique SA McDowell, Randall L. Price, A. Thomas Ghuman, Ashish G. Sharma, Paul A. Raskauskas, Joseph P. Walker, Kristi Maro, Lee T Toleman, Cheryl Kiesel, Crystal Y. Peters, Cheryl Ryan, Eileen Knips, Anita H. Leslie, Alice Arevalo, Raymond K. Kiesel, Nader Moinfar, Scott M. Friedman, Shannon M Rehling, Ceara L Wendel, Damanda F. Fagan, Kimberly A. Williamson, Jacqueline Andrews, Karen L Seyez, Shana E Williams, Allen McKinney, Brenda J. Bobbitt, Victor Hugo Gonzalez, Nehal R. Patel, Rohit Adyanthaya, Yesenia Salinas, Nancy L Salinas, David A. Reyes, Elyssa Navarro, Angelina Garza, Amber B Ibarra, Ana L Pina, Brenda Velasquez, Isaac Cabrera, Janette Arredondo, Monica R. Cantu, Enrique Chavez, Rebecca R. Flores, Yvonne Diaz, Samuel Alonso, Santos Garza, Stephanie Tamez, Monique Montemayor, Justin H. Townsend, Jessica Taha, Belen Rodriguez, Ailen E Gutierrez, Alexey Gomez Rodriguez, Enelda Idalia Mendoza, Liliana P. Perez, Megan Mawdesley, Shannon B Asklar, Tanya Nicole Rego, Brandon Michael Sparling, Ailen Graces Fernandez, J. Peter Campbell, Steven T. Bailey, Christina J Flaxel, Andreas K. Lauer, Thomas S. Hwang, Mitchell Schain, Ann D. Lundquist, Shirley D. Ira, Jennifer K Maykoski, Scott R. Pickell, Chris S Howell, Chiedozie Ukachukwu, Dawn M. Ryan, Jordan Barth, Jocelyn T. Hui, Jamin S. Brown, G. Robert Hampton, Laurie J. Sienkiewycz, Christine M. Dorr, Lisa Spuches, Michelle L. Manley, Lynn M. Kwasniewski, Nicole E. Robarge, Stefanie R. DeSantis, Teresa M. DeForge, Jeffrey P Barker, Abigail Miller, Ruben A. Grigorian, Latha M Jois, Rebecca Webb, Rebecca Morris, Sharoon David, Dusti D Douglas, Faith Pena, Cameron McLure Stone, McCayla Elise Hall, Andrea K. Menzel, Monica Hamrick, Lea R. Raymer, Leslie D. Rickman, Donna Machen, Julia Crokett Overbey, Lisa H. Hawkins, Melissa Smith, Paula A. Price, Alan F. Cruess, John D. Dickinson, R. Rishi Gupta, Alec M Cranston, Meggie D Caldwell, Stacey Durling, Trina MacDonnell, Mitzi Hynes, Gregory M. Fox, Blake A. Cooper, David S. Dyer, Ivan R. Batlle, Ryan D. Christensen, Ravi S. J. Singh, Lexie R. Ainley, Karla A. Batlle, Holly A Hinkel, Holly Wyrick, Amber R VandeVelde, Frank T. Yeager, Katherine Pippin, Michel Shami, Yolanda Saldivar, Ashaki Meeks, Glenn R Gardner, Karl R. Olsen, Jared E. Knickelbein, Robert L. Bergren, Bernard H. Doft, Lori A. Merlotti, Lois Stepansky, Julie Walter, Phyllis P Ostroska, Dawn Diperna, Clement K. Chan, Maziar Lalezary, Tiana Gonzales, Tonya M Gieser, Kimberly S. Walther, Isela Aldana, Lenise E. Myers, Kristina Pettit, Kenneth M. Huff, Jason M. Handza, Bronson Oudshoff, Christina Glover, Corey T. McGahee, Annette M. Carey, Tirso M. Lara, Stuart K. Burgess, Noel H. Pereda, Adriana Villa, Deborah Davis, Karen Workman, Mark Oberlander, Apurva K. Patel, Colin Ma, Mark A. Peters, Paul S. Tlucek, Brian S Puckett, Pualani Smith, Stephanie L. Ho, Margaret E Charpentier, Marcia Kopfer, Christine Hoerner, Melvin Chen, Peggy A. Jelemensky, Samantha R. Basham, Tara L. Raphael, Rosa Miller, Mark Sneath, Jawad A. Qureshi, Johnathan D. Warminski, Kruti P. Dajee, Gregory A Dunn, Victoria E. Cowart, Andre Watkins, Diana Murillo, Denise Ortiz, Eduardo Vitor Navajas, Sijia Cao, Mira Jovanovic, Theresa Wiens, Sherry Han, Kelly Grant, Anne-Marie Godfrey, Bryan Harrison, Sharon D. Solomon, Susan Bressler, Mary Frey, Deborah Donohue, Lisa K. Levin, Dennis Cain, Russ Distle, Alice T. Lyon, Manjot K. Gill, Nicole M Seddon, Priya M Thakkar, Chisomo Mwale, Carmen Ramirez, Crystal Santillanes, Evan C Davies, Julie Pecht, Anson Moore, Cason Moore, Kaitlyn Veto, Maritza Barragan, Evica Simjanoski, Jennifer I. Lim, Felix Y. Chau, Jie Sun, Natasa Stankovic, Tametha Johnson, Ben Martinez, Andrea Degillio, Mark Janowicz, Sandeep Grover, Ghulam Shabbir Hamdani, Jazzmin N Smith, Romesh Babaria, Bharani Krishna Mynampati A, Justin Gottlieb, Barbara A. Blodi, Kristine A. Dietzman, Christopher M. Smith, Angela M. Adler, Denise A. Krolnik, Sandie L. Reed, Ronald C Gentile, John Bo Soo Choi, Melissa Rivas, Robert Masini, Wanda Carrasquillo-Boyd, John T. Lehr, Brittany M. Pendarvis, Mari Delgado, Martha Eileen Haddox, Patricia Lynch, Robert Atnip, Atira Bramble, Ashley E Willer, Chase Hutchings, Julian Rodriguez, Kyle Dreessen, Mark Pena, William N. Rosenthal, Elizabeth N. Heim, Sarah N. Lamaster, Mary C Stewart, R. Scott Varner, Courtney J Dunn, Moises A. Chica, Calvin E. Mein, Lydia Adams, Lita Kirschbaum, Jenny M Bermea, Sara L Cloudt, Victoria Lopez, Jonathan San Roman, Samantha Bankston, Christopher Sean Wienecke, Brenda Nakoski, Ramanath Bhandari, Jennifer Shaw, Bradley C. Evans, Gaylan W Moushon, Amanda Fox, Braden Anderson, Caitlyn Wessel, Dennis Frye, Kris Karrick, Abdhish R. Bhavsar, Andrea Gilchrist, Celeste Moreno, Jason R Sweet, Matt D. Peloquin, Denise Vang, Erin C. Kinney, Alanna C. Evans, Gregory M. Haffner, Andrea L. DeClement, Leslie D Hurst, Patricia L Anderson, Stephanie Esteves, Adriana N Enxuto, Emily Morse, John B. Christoforidis, Jill Brickman-Kelleher, Sue A. Bulau, Patricia H Fryer, Dennis Haymore, John A. Wells, Tiffany R. Swinford, Tiffany N. Ogbuewu, Robbin Spivey, Ashley Studebaker, Jared S. Nielsen, Kyle J. Alliman, Tami Jo Woehl, Marianne Parker, Erin L Riley, Jack Bowers, Paula L Bix, Jamie Spillman, Spencer D Ridgway, Lisa M. Boender, Roy W. Beck, Alyssa Baptista, Wesley T. Beaulieu, Claire T. Calhoun, Sharon R. Constantine, Isabella Correia, Brian B. Dale, Simone S. Dupre, Crystal A. Franklin, Sandra Galusic, Meagan Huggins, Brenda L. Hunter, Paula A. Johnson, Brittany Kelly, Maureen G. Maguire, Britney Meadows, Alice Zokruah, Danni Liu, Carin M. Preston, Sangeeta Bhargava, Andrew J. Barkmeier, Darrell Baskin, Barbra Blodi, Emily Chew, Frederick L. Ferris, Glenn J. Jaffe, Neil M. Bressler, Brandon Lujan, Judy E. Kim, Mathew W. MacCumber, Gary Abrams, Deborah Barnbaum, Harry Flynn, Kyle Rudser, Paul Sternberg, Ruth Weinstock, Stephen Wisniewski
Journal: JAMA (2023)

Importance Anti–vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53) without CI-DME. Interventions Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P &amp;amp;lt; .001). The mean (SD) change in visual acuity from baseline to 4 years was −2.7 (6.5) letters with aflibercept and −2.4 (5.8) letters with sham (adjusted mean difference, −0.5 letters [97.5% CI, −2.3 to 1.3]; P = .52). Antiplatelet Trialists’ Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance Among patients with NPDR but without CI-DME, at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration ClinicalTrials.gov Identifier: NCT02634333